DNA Double-Strand Breaks Repair and Signaling of Human Gliomas and Normal Brain Cells in Response to Radiation: Potential Impact of the ATM- and BRCA1- Dependent Pathways
نویسندگان
چکیده
Deriving from glial, astrocyte, or dendrocyte cells, gliomas are the most frequent tumors of central nervous system. Unfortunately, most of gliomas are refractory to standard radiotherapy treatments. The median survival for patients bearing grade IV gliomas (glioblastomas) does not exceed one year even after both aggressive surgery and radiotherapy treatment (Behin et al., 2003). A standard of 60 Gy delivered in 30 fractions during six weeks remains the best radiotherapy modality against gliomas (Behin et al., 2003). This last conclusion raises the possibility that human gliomas might be generally more radioresistant than other tumor tissues. However, there is no consensus in literature about a specific radioresistance of human gliomas. Besides, the complexity of the molecular and cellular features of radiation response and the difficulty to define reliable endpoints to account for radiosensitivity whatever the tissue type may have limited the extent of some reports. In addition, three specific features of radiobiology of gliomas can be also evoked: cellular in vitro endpoints like clonogenic survival seem to be less appropriate to predict gliomas radiocurability than that of other tumour types (Taghian et al., 1992, 1993); animal models extensively used in glioma research may not reflect specificities of human gliomas and may bias in anti-glioma strategies (Holland, 2001); DNA repair capacity of gliomas is poorly documented and most of the investigations about genes mutations concern actors of proliferation rather than upstream DNA repair proteins (Zhu & Parada, 2002). In 2004, our group obtained the most protracted survival of rats bearing radioresistant rodent gliomas by using synchrotron X-rays combined with intracerebral cisplatin injection. Such so-called PAT-plat treatment triggers the photoactivation of platinum atoms and produces some additional DNA double-strand breaks (DSBs) at the vicinity of cisplatininduced DNA adducts (Biston et al., 2004). The severity of PAT-Plat-induced DSBs was shown to be due to the inhibition of the major DSB repair pathway in mammalians, namely
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